Impact of freshwater river reconnection on porewater salinity and ammonium availability in coastal brackish marsh soils.

Restoring freshwater flows to wetland ecosystems is an increasingly common tool for reversing saltwater intrusion/chronic salinization. Hydrologic restoration projects can deliver large volumes of sediment and fresh water to coastal basins, episodically exposing brackish and salt marsh vegetated soils to low surface water salinities. Yet little is known about the impacts of river reconnection/diversions to porewater salinity of the active root zone (0-30 cm) and salinity dependent soil biogeochemical processes like sorption. Intact soil cores from a brackish marsh site in mid-Barataria Basin, LA were subjected to a simulated river diversion opening to examine how porewater salinity and ammonium (NH4+) availability change with depth and time. Quadruplicate soil cores were inundated with continuously flowing fresh (0 salinity) water for 0, 7, or 28 d then measured for porewater salinity and NH4+ partition coefficient (exchangeable NH4+:porewater NH4+) every 2 cm for the top 10 cm of soil. Porewater salinity decreased in the 0-4 cm interval between 0 and 7 d of the simulated river diversion and increased in the 8-10 cm interval between 7 and 28 d. Overall, depth-averaged porewater salinity of the top 10 cm did not significantly change between 0 and 28 d of the simulated river diversion. Ammonium partition coefficients increased only in the 0-2 cm interval between 0 and 7 d of the simulated river diversion, likely due to freshening-induced NH4+ adsorption. These results indicate that the physicochemical environment of brackish marsh soils is relatively resistant to a single surface water freshening over one month. Models utilized by the state of Louisiana may be overpredicting freshening of the marsh soil porewater in Mid-Barataria Basin in response to the episodic operation of the Mid-Barataria Sediment Diversion. This study demonstrates the importance of measuring diffusive-adsorptive flux of major cations and anions when modeling vertical salt transfer in brackish marsh soils.

An industry perspective approach and control strategy for implementation of ready-to-use cells in bioassays: survey outcome and recommendations.

The BioPhorum Development Group is an industry collaboration enabling the sharing of common practices for the development of biopharmaceuticals. Bioassays are an important part of an analytical control system. Utilization of ready-to-use cells can increase operational flexibility and improve efficiency by providing frozen cell banks uniform stock while removing challenges associated with maintaining cultured cells. The BioPhorum Development Group-Bioassay workstream conducted an intercompany benchmarking survey and group discussions around the use of ready-to-use cells for bioassays. The results of the collaboration provide alignment on nomenclature, production, qualification and implementation of ready-to-use cells to support the assay life cycle.

Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants.

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (Ki ~2 µM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC0-96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC50 , 0.37-12 µM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered.

Temporally-displaced Mississippi River spring flood pulse shows muted aquatic ecosystem response in estuarine waters: A climate change warning for coastal foodwebs.

Mississippi River water levels typically rise in the early spring after snow melt in the extensive watershed. However, in 2016, warm air temperatures coupled with high precipitation led to a historically early river flood pulse, resulting in the opening of a flood release valve (Bonnet Carré Spillway) in early January to protect the city of New Orleans, Louisiana. The goal of this research was to determine the ecosystem response of this wintertime nutrient flood pulse on the receiving estuarine system and compare it to historical opening responses, which are generally several months later. Nutrients, TSS, and Chl a were measured along a 30 km transect in the Lake Pontchartrain estuary, before, during, and after the river diversion event. In the past, NOx concentrations were quickly reduced to below detection in the estuary in <4 weeks post-event accompanied by a moderate phytoplankton bloom. However, due to seasonal limitations (cold water temperatures and light limitation) during the 2016 event, NOx remained elevated for >2 months post-closure and Chl a values were low, indicating limited assimilation of nutrients into phytoplankton biomass. Consequently, much of the bioavailable nitrogen was denitrified by sediments and dispersed to the coastal ocean over time, limiting the transfer of nutrients into the food web by means of a spring phytoplankton bloom. An increasing warming trend in temperate and polar river watersheds is leading to earlier spring flood pulses, altering the timing of coastal nutrient transport, decoupled from conditions supporting primary production, which could significantly affect coastal food webs.

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 µM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Impacts of land uses on spatio-temporal variations of seasonal water quality in a regulated river basin, Huai River, China.

Land use impacts from agriculture, industrialization, and human population should be considered in surface water quality management. In this study, we utilized an integrated statistical analysis approach mainly including a seasonal Mann-Kendall test, clustering analysis, self-organizing map, Boruta algorithm, and positive matrix factorization to the assessment of the interactions between land use types and water quality in a typical catchment in the Huai River Basin, China, over seven years (2012-2019). Spatially, water quality was clustered into three groups: upstream, midstream, and downstream/mainstream areas. The water quality of upstream sites was better than of mid-, down-, and mainstream. Temporally, water quality did not change significantly during the study period. However, the temporal variation in water quality of up-, down-, and mainstream areas was more stable than in the midstream. The interactions between land use types and water quality parameters at the sub-basin scale varied with seasons. Increasing forest/grassland areas could substantially improve the water quality during the wet season, while nutrients such as phosphorus from cropland and developed land was a driver for water quality deterioration in the dry season. Water area was not a significant factor influencing the variations of ammonia nitrogen (NH3-N) and total phosphorus (TP) in the wet or dry season, due to the intensive dams and sluices in study area. The parameters TP, and total nitrogen (TN) were principally linked with agricultural sources in the wet and dry seasons. The parameters NH3-N in the dry season, and chemical oxygen demand (CODCr) in the wet season were mainly associated with point source discharges. Agricultural source, and urban point source discharges were the main causes of water quality deterioration in the study area. Collectively, these results highlighted the impacts of land use types on variations of water quality parameters in the regulated basin.

Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants.

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1-2 vs. 2.5-4.5 h), lower area under the plasma concentration-time curve (430-490 vs. 794-5120 nM × h), longer terminal half-life (24-45 vs. ~12-18 h), and higher apparent volume of distribution during the terminal phase (960-12,700 vs. ~46-130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.

Interactive influences of meteorological and socioeconomic factors on ecosystem service values in a river basin with different geomorphic features.

Ecosystem service value (ESV) is influenced by land use and land cover (LULC), and is closely related to natural conditions and human activities. However, the interactions between human and natural systems and ESV remain unclear, especially concerning widely discussed meteorological and socioeconomic factors. In this study, three periods of LULC patterns (2000, 2010, and 2020) in the Haihe River Basin, northern China, were collected to determine the relationship between changes in LULC and ESV over time. Natural and socioeconomic data associated with ESV were obtained and the structural equation model was used to decouple interactions between these factors. Results showed that the total value of regional ecosystem services has decreased as cultivated land shrunk and artificial surfaces increased over the past two decades. The ESV was significantly decreased in the middle of the basin. The direct effects of meteorological factors and socioeconomic factors on ESV were positive (0.094) and negative (-0.203), respectively. The indirect effect of socioeconomic factors on ESV through meteorological and LULC factors was 0.149. Structural equation modeling demonstrated that under the dominance of LULC, interactions between natural and socioeconomic factors affected ESV in a complex manner. These results implied that identifying the direct and indirect effects of economic development and human activities on ESV could guide and implement effective land management policies.

Novel methods to determine complement activation in human serum induced by the complex of Dezamizumab and serum amyloid P.

Lack of simple and robust methods to determine complement activation in human serum induced by antigen-antibody complexes is a major hurdle for monitoring therapeutic antibody drug quality and stability. Dezamizumab is a humanized IgG1 monoclonal antibody that binds to serum amyloid P component (SAP) for potential treatment of systemic amyloidosis. The mechanism of action of Dezamizumab includes the binding of SAP, complement activation through classical pathway, and phagocytosis; however, the steps in this process cannot be easily monitored. We developed two novel methods to determine Dezamizumab-SAP complex-induced complement activation. Complement component 3 (C3) depletion was detected by homogeneous time-resolved fluorescence (HTRF), and C3a desArg fragment, formed after the cleavage of C3 to yield C3a followed by removal of its C-terminal arginine residue, was determined using Meso Scale Discovery (MSD) technology. We found that the presence of both Dezamizumab and SAP was required for complement activation via both methods. The optimal molar ratio of Dezamizumab:SAP was 6:1 in order to obtain maximal complement activation. The relative potency from both methods showed a good correlation to Dezamizumab-SAP-dependent complement component 1q (C1q) binding activity in Dezamizumab thermal-stressed samples. Both SAP and C1q binding, as determined by surface plasmon resonance and the two complement activation potency methods described here, reflect the mechanism of action of Dezamizumab. We conclude that these methods can be used to monitor Dezamizumab quality for drug release and stability testing, and the novel potency methods reported here can be potentially used to evaluate complement activity induced by other antigen-antibody complexes.

Soil acidification enhances the mobilization of phosphorus under anoxic conditions in an agricultural soil: Investigating the potential for loss of phosphorus to water and the associated environmental risk.

Soil redox potential (EH) and pH are key parameters regulating the solubility and fate of phosphorus (P). However, the impact of soil acidification on the redox-induced mobilization and speciation of P in soils under a wide range of EH values has not been extensively studied. Here, we investigated the mobilization and speciation of P in an acidified agricultural soil at two different pH values (e.g., highly acidic soil; pH = 5.6 and slightly acidic soil; pH = 6.1) compared to the un-acidified soil (control soil; pH = 7.3) under a wide range of EH condition (+459 to -281 mV). The impacts of EH/pH-dependent changes of Fe-Mn oxides, and dissolved organic (DOC) and inorganic (DIC) carbon on P mobilization and speciation were also investigated using geochemical and spectroscopic (X-ray absorption near edge structure) techniques. The concentrations of dissolved P under anoxic conditions increased up to 69.3% in the highly acidic soil compared with the control soil. The decrease of the Fe-P fraction, the decrease of Ferrihydrite-Pads speciation, and the strong linear correlation between the dissolved P and Fe2+ (R2 > 0.85) supports the finding that enhanced P mobilization under anoxic conditions may be attributed to Fe reduction in the highly acidic soil. The concentration of dissolved Fe and P remained low until pH dropped below 6.35 for P and 6.28 for Fe, while a liner increase was found in dissolved Mn accompanying a general trend of pH decrease. This result suggests that the dissolution of reducible Mn under acidic soil conditions was an important factor for enhancing mobilization of dissolved P under anoxic conditions. This trend was due to the low amount of Mn, indirectly speeding up Fe reduction. These results can help to develop management practices to effectively mitigate P export and protect water resources from diffuse P pollution.

Peripheral freshwater deltaic wetlands are hotspots of methane flux in the coastal zone.

Methane (CH4) emissions are low in the coastal zone due to a higher redox poise, related to sulfate reduction. However, river deltas are a potential source of CH4 flux in coastal zones globally, due to fresh condition and high primary production. The goal of this study was to seasonally measure CH4flux at three different geomorphic settings (newly forming island, river channel bottom and established freshwater marsh) within the Wax Lake Delta, Louisiana, USA. CH4 flux rates were 386 ± 327 mg C m-2 d-1 in March and 2859 ± 1286 mg C m-2 d-1 in June at the freshwater marsh site. At the island site, CH4 flux was significantly smaller at 7.94 ± 3.57 mg C m-2 d-1 in March and 215 ± 153 mg C m-2 d-1 in June while at adjacent river channel bottom site, CH4 flux was lowest at 2.49 ± 3.38 mg C m-2 d-1 in March and 19.5 ± 1.12 mg C m-2 d-1 in June at the air-water interface. CH4 emission rates show significant spatial heterogeneity with rates up to two orders of magnitude greater at the marsh site at the periphery of the delta, related to greater soil total C. Therefore regions within the active delta do not provide a significant source of methane, due to a lack of soil C, despite freshwater conditions. However, marshes at the periphery within the halo of fresh water, populated with established plant communities can be significant hotspots of CH4 emissions, despite their location within the coastal zone.

Structure and Functional Characterization of a Humanized Anti-CCL20 Antibody following Exposure to Serum Reveals the Formation of Immune Complex That Leads to Toxicity.

mAbs have revolutionized the treatment of autoimmune disorders. Even though mAbs have shown impressive efficacy in blocking T cell or B cell activation and/or recruitment to sites of inflammation, this group of biologicals are not devoid of adverse effects. The most serious adverse effects include infusion reactions, including the activation of the complement pathway. In this study, we present a detailed structure-function study of an anti-CCL20 humanized IgG1 mAb that neutralizes CCL20 chemokine and prevents the recruitment of Th17 cells to sites of inflammation. We demonstrate that the anti-CCL20 Ab changes significantly following administration to humans and monkeys and exposure to human serum. Analysis of the drug product revealed that the anti-CCL20 Ab has unexpectedly high C1q binding. This high binding was linked to immune complex formation in vivo but not during in vitro serum incubation. The immune complex contained multiple complement components. Anti-CCL20 Ab-mediated, complement-dependent cytotoxicity occurred when the Ab bound to CCL20 tethered to the cell membrane of target cells. Taken together, these results provide a likely cause for the animal toxicity observed. In addition, anti-CCL20 revealed progressive acidification because of N100 (located in CDR) deamidation over time, which did not directly impact Ag binding. Our study demonstrates that the safety profiling of mAbs should include the evaluation of effector functions in addition to typical stressed conditions.

Experimental bluetongue virus infection of Culicoides austropalpalis, collected from a farm environment in Victoria, Australia.

Following the emerging bluetongue virus transmission in European temperate regions, we question the vector competence of the abundant Culicoides austropalpalis Lee and Reye in South-East temperate Australia. Field collected Culicoides midges were membrane fed with a bluetongue virus serotype 1 (BTV-1). The average feeding rate was 50%. After 13 days, survival rate was 25% and virus RNA presence was checked by quantitative PCR targeting viral genome segment 10. Virus RNA was found in 7.4% of individually tested females with relative viral RNA load values lower than freshly fed females, indicating that viral replication was low or null. A second qPCR targeting viral genome segment 1 confirmed the presence of virus RNA in only four out of 29 previously positive specimens. After 10 days culture on Culicoides cells, none of these four confimed positive samples did show subsequent cytopathogenic effect on Vero cells or BTV antigen detection by ELISA. As control for this virus activity detection, 12 days after microinjection of BTV-1, Culex annulirostris mosquitoes showed, after culture on Kc cells, cytopathogenic effect on Vero cells, with ELISA-confirmed infection. Despite its abundance in farm environment of the temperate Australian regions, the results of this study make C. austropalpalis of unlikely epidemiological importance in the transmission of BTV in Australia.

Assessment of Regular and NPH Insulin Concentration via Two Methods of Quantification: The Washington State Insulin Concentration Study (WICS).

BACKGROUND: Recent reports have suggested that insulin vials purchased in community pharmacies do not meet the minimum required intact insulin concentration (≥95 U/mL) as defined by the United States Pharmacopeia. We sought to independently obtain multidose human insulin vials from a variety of community pharmacies across the state of Washington and quantitatively measure intact insulin. METHODS: Sixty 10-mL vials of insulin (n = 30 regular human insulin and n = 30 neutral protamine Hagedorn insulin) were purchased and assayed. To ensure random selection of lots and supply chain sources, insulin samples were purchased on a variety of calendar dates from various pharmacy locations across Washington State, inclusive of both chain and independent pharmacies. All samples were assessed for intact insulin concentration via both Ultra Performance Liquid Chromatography coupled with UV detection (UPLC-UV) and Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). RESULTS: When considering all samples (N = 60), the mean concentration was 101.8 ± 4.4and 91.5 ± 1.9 U/mL as determined by UPLC-UV and UPLC-MS, respectively. Measured concentrations ranged from 90.0 to 108.4 U/mL when assayed by UV UPLC and 86.1 to 95.4 U/mL for UPLC-MS. CONCLUSION: To our knowledge, this is the first study following the report by Carter et al that assessed human insulin concentrations by both UPLC-UV and UPLC-MS. These findings are important because they demonstrate that the results obtained from these two methods differ and that the method used must be considered when interpreting findings.

Long-term fate of rapidly eroding carbon stock soil profiles in coastal wetlands.

Marsh edge erosion is one of the major causes of land and associated carbon loss in wetland-dominated coastlines. Assessing carbon stocks and understanding fate of eroding carbon is an essential component of wetland carbon budget. This study aims to understand the vertical soil carbon profile of an eroding marsh and potential mineralization of carbon in estuaries. Eleven soil cores (~2 m deep) were collected from the edge of four highly eroding marsh sites and three cores from the estuarine bottom (~50 cm deep). Cores were sectioned into 10-cm intervals and analyzed for total, labile and refractory carbon, carbon density, select enzyme and microbial activities, and organic and inorganic phosphorus forms. The total carbon, labile carbon, and carbon density increased with depth at all sites. The carbon density at 1-1.5 m deep (0.04 ± 0.003 g cm-3) was significantly higher (p < 0.0001) than the top 1 m soil (0.032 ± 0.002 g cm-3), indicating the need for considering deeper carbon profile for blue carbon stock assessment. The age of the carbon at the estuarine bottom was 388 ± 84 years before present (ybp) indicating the recently eroded wetland carbon is not reburied in the estuary. Significant anaerobic microbial activity was present at all the soil depths suggesting high potential of mineralization of eroded carbon in the aerobic estuarine water. The coastlines experiencing high relative sea-level rise at present or coastlines that are projecting high sea-level rise in the near future are susceptible to losing an enormous amount of previously sequestered carbon over a relatively short period of time.

Bluetongue virus serotype 12 enters Australia - a further incursion of novel western lineage genome segments.

Bluetongue virus (BTV) is an arbovirus (genus: Orbivirus) that occurs worldwide. It infects domestic and wild ruminant species and can cause disease in livestock, producing high economic impact. Recently, it gained extra prominence throughout Europe, with disease occurring in regions traditionally free of BTV. BTV enters Australia from Southeast Asia via wind-borne infected Culicoides spp. The first Australian isolation was 1975 (BTV-20) and further serotypes were isolated between 1979-86 (BTV-1, -3, -9, -15, -16, -21, -23). Despite increased, more sensitive, monitoring, no more were detected in over two decades, implying a stable BTV episystem of eastern ancestry. Isolations of BTV-2, -7 and -5 then occurred between 2007-15, with the latter two possessing genome segments with high sequence identity to western isolates. We report on the first isolation and genomic characterization of BTV-12, which revealed that three more novel western topotype gene segments have entered northern Australia.

Investigating the impact of in situ soil organic matter degradation through porewater spectroscopic analyses on marsh edge erosion.

Marsh edge erosion results in soil organic matter (SOM) loss from coastal wetlands and is differentially affected by wind waves, soil properties, and vegetation cover. The degradation of SOM may make the marsh edge susceptible to erosion. The objective of this study was to investigate the effect of in situ biogeochemical degradations of SOM on marsh edge erosion using porewater spectroscopic analyses. Edge erosion was monitored at 12 transects in one of the highly eroding coastal basins of Louisiana. A total of 36 cores were collected at different distances from the edge of the marsh. Porewater was extracted and analyzed for dissolved organic carbon (DOC) and spectroscopic indicators. The north and west side had greater erosion rates (102.38 ± 5.2 cm yr-1) than east and south side (78.47 ± 3.3 cm yr-1). However, the north and east side had greater DOC and refractory carbon but less microbial activity indicating SOM degradation alone did not correlate to edge erosion. The intersecting trend between erosion rate and SOM degradation among four sides of the island indicates the complex nature of edge erosion drivers. The estuarine bottom indicators suggest the eroded SOM is not reburied but rather degraded and emitted back into the atmosphere as CO2, potentially contributing to global change. The coastlines projected to experience high sea-level rise in the coming century are vulnerable to losing a large amount of stored carbon in the absence of efficient mitigation measures.

Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail.

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P-glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter-expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration-time curve (AUC0-inf ) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35-1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2-K) AUC0-inf (GMR, 0.77 (0.71-0.83)); and had no effect on metformin half-life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro-in vivo prediction accuracy, contributing to a standard approach for studying transporter-mediated natural product-drug interactions.

The impact of recently excavated dredge pits on coastal hypoxia in the northern Gulf of Mexico shelf.

Large volumes of sand are needed in order to combat coastal land loss due to global sea-level rise for restoration of barrier island systems and beaches undergoing rapid erosion and submergence. The sediment required for such projects often originates from dredging of sand deposits on the adjacent shelf. Two dredge pits, with contrasting geology and located at varying distances from the Mississippi River Delta in the northern Gulf of Mexico shelf were sampled during spring and summer. Samples were also collected concurrently from surrounding continental shelf stations that are subject to seasonal hypoxia every summer. The bottom water dissolved O2 inside the dredge pits were found to be consistently hypoxic or near hypoxic throughout both seasons, with high sediment O2 consumption (SOC) rates of 23.7 to 51.8 mmol m-2 d-1 in spring and 34.3 to 51.3 mmol m-2 d-1 in summer. In contrast, control stations immediately outside the dredge pits showed lower SOC rates ranging between 6.3 and 35.9 mmol m-2 d-1. The SOC rates of the surrounding continental shelf subjected to annual seasonal hypoxia ranged between 25.7 and 59.6 mmol m-2 d-1 indicating that the dredge pits experienced similar high rates of SOC. Our results suggest that sluggish water circulation inside these topographic depressions coupled with higher SOC rates does result in persistent low bottom O2 conditions inside these dredge pits well beyond the duration of the seasonal hypoxia period in this region. This is the first study to provide insight on the impacts of dredge pits to surrounding hypoxia in this region which is critical as future dredging operations are expected to increase worldwide with projected sea-level rise.